Affinage

SKP2

S-phase kinase-associated protein 2 · UniProt Q13309

Length
424 aa
Mass
47.8 kDa
Annotated
2026-06-10
100 papers in source corpus 46 papers cited in narrative 46 extracted findings
Cross-family judge vs UniProt: Affinage preferred faithfulness: 6/6 claims corpus-supported (100%)

Mechanistic narrative

Synthesis pass · prose summary of the discoveries below

SKP2 is the substrate-recognition F-box subunit of the SCF(SKP2) E3 ubiquitin ligase that drives G1/S cell cycle progression by targeting cyclin-dependent kinase inhibitors for destruction (PMID:15520280). Its best-defined activity requires the accessory protein CKS1, which binds SKP2 directly through eight residues across two discrete regions and dramatically enhances recruitment of Thr187-phosphorylated p27KIP1, reconstituting K48-linked ubiquitination of p27 in a fully purified system (PMID:11231585, PMID:15452136); a CKS1-independent SKP2 N-terminal motif also engages cyclin A within CDK2–cyclin A complexes to fine-tune p27 turnover (PMID:33422522). Genetic epistasis establishes p27 as the principal downstream effector through which SCF(SKP2) controls proliferation and cell size (PMID:15520280), and SKP2 extends this control to additional cell-cycle and chromatin regulators including p130, p57Kip2, macroH2A1, and IDH1/2, the last coupling cell-cycle phase to metabolic oscillation between glycolysis and the TCA cycle (PMID:12717421, PMID:38102140, PMID:25818643, PMID:32669607). Beyond proteolytic K48-linked ubiquitination, SKP2 catalyzes non-degradative K63-linked ubiquitination of substrates such as AKT, YAP, and Lkb1 to enhance their activity, localization, and downstream signaling (PMID:29535262, PMID:29891922, PMID:36930164), and acts as an adaptor coupling IKKβ to selective autophagy (PMID:29474632). SKP2 abundance and subcellular distribution are heavily regulated post-translationally: p300-mediated acetylation at K68/K71 (reversed by SIRT3) impairs Cdh1-dependent proteolysis and drives cytoplasmic retention, where SKP2 degrades E-cadherin to promote migration (PMID:22770219), while OGT-mediated O-GlcNAcylation at Ser34 stabilizes SKP2 and enhances SKP1 binding (PMID:38396292). Multiple deubiquitylases (USP2, USP10, USP18) and protein partners (pVHL, AR, FAK) tune SKP2 stability (PMID:34425107, PMID:34599966, PMID:30858391, PMID:21358672, PMID:18628304), and its transcription is governed by E2F, GABP, YAP, NUCKS1, and lineage-specific factors (PMID:16331253, PMID:12907639, PMID:28673931, PMID:34845229). Through these activities SKP2 functions as an oncogenic node coordinating proliferation, migration, metabolism, and survival across diverse tissues.

Mechanistic history

Synthesis pass · year-by-year structured walk · 22 steps
  1. 2001 High

    Established the minimal biochemical requirements for SCF(SKP2) substrate recognition by showing CKS1 is an obligate cofactor bridging SKP2 to phosphorylated p27.

    Evidence Fully reconstituted in vitro ubiquitination with purified components and binding assays

    PMID:11231585

    Open questions at the time
    • Did not define which SKP2 residues form the CKS1 interface
    • Substrate scope beyond p27 not addressed
  2. 2001 High

    Placed SKP2 as the effector linking extracellular adhesion and growth-factor cues to cell-cycle entry by showing ectopic SKP2 overrides adhesion dependence to degrade p27 and drive S-phase.

    Evidence Ectopic expression and loss-of-adhesion assays with cell-cycle readout

    PMID:11425869

    Open questions at the time
    • Mechanism connecting adhesion signaling to SKP2 abundance not defined
  3. 2003 Medium

    Expanded SKP2 substrate range beyond p27 to p130 and Myc and revealed a non-catalytic transcriptional coactivator role for Myc.

    Evidence Co-IP, ubiquitination assays, transcriptional reporter assays

    PMID:12717421 PMID:12769843

    Open questions at the time
    • Physiological weighting of these substrates versus p27 unresolved
    • Coactivator mechanism not structurally defined
  4. 2003 Medium

    Identified transcriptional control of SKP2 by demonstrating cell-cycle-dependent promoter occupancy by GABP and induction by E2F1.

    Evidence EMSA, ChIP, promoter-reporter, gain/loss-of-function

    PMID:12907639 PMID:16331253

    Open questions at the time
    • Interplay between multiple SKP2 transcription factors not integrated
  5. 2004 High

    Defined the CKS1-binding interface on SKP2 and established p27 as the principal in vivo SCF(SKP2) effector via genetic epistasis.

    Evidence Site-directed mutagenesis with in vitro ubiquitination; Skp2-KO vs Skp2-KO/p27T187A knock-in mice

    PMID:15452136 PMID:15520280

    Open questions at the time
    • Tissue-specific substrate contributions outside hepatocytes not tested
  6. 2008 Medium

    Showed SKP2 stability is set by oncogenic upstream regulators, with AR blocking D-box-dependent SKP2 degradation to drive prostate cancer proliferation.

    Evidence Co-IP, ectopic expression, siRNA/dominant-negative, proliferation assays

    PMID:18628304

    Open questions at the time
    • Direct E3 mediating D-box degradation not defined in this study
  7. 2011 Medium

    Identified pVHL as a non-canonical destabilizer of SKP2 that antagonizes Akt-mediated stabilizing phosphorylation, linking SKP2 turnover to DNA damage.

    Evidence Co-IP, half-life assay, mutagenesis, VHL-null RCC reconstitution

    PMID:21358672

    Open questions at the time
    • Mechanism of E3-independent destabilization not resolved
  8. 2012 High

    Revealed acetylation as a switch controlling SKP2 localization and a non-canonical cytoplasmic function, with p300/SIRT3-regulated K68/K71 acetylation driving E-cadherin degradation and migration.

    Evidence Mass spec, acetyl-mimetic/dead mutants, fractionation, migration and in vivo tumorigenesis assays

    PMID:22770219

    Open questions at the time
    • Cytoplasmic substrate repertoire beyond E-cadherin not catalogued
  9. 2015 High

    Connected SKP2 to chromatin and G2/M control through a Skp2–macroH2A1–CDK8 feedback axis enhancing p27 degradation.

    Evidence Co-IP, ubiquitination assay, mouse tumor models with genetic rescue

    PMID:25818643

    Open questions at the time
    • Direct enzymatic step of mH2A1 ubiquitination relative to chromatin context not detailed
  10. 2016 High

    Established SKP2 as a nutrient-responsive coupler of cell cycle to autophagy by degrading CARM1 under nutrient-rich conditions, with AMPK/FOXO3a repressing SKP2 during starvation.

    Evidence Co-IP, ubiquitination assay, ChIP, genome-wide analysis, AMPK modulation

    PMID:27309807

    Open questions at the time
    • Quantitative threshold of SKP2 repression needed to license autophagy not defined
  11. 2016 Medium

    Showed SKP2 can protect substrates by antagonizing alternative E3s, shielding JARID1B and EZH2 from TRAF6-mediated K63 ubiquitination.

    Evidence Co-IP, K63-ubiquitination assays, TRAF6 catalytic-dead mutant, mouse prostate tumor models

    PMID:25596733 PMID:27869166

    Open questions at the time
    • Direct biochemical mechanism of SKP2 shielding (competition vs modification) unresolved
  12. 2017 High

    Defined SKP2 K63-linked ubiquitination as an activating modification for substrates, stabilizing MTH1 and driving YAP nuclear activity independently of Hippo signaling.

    Evidence Site-specific mutagenesis, K63-ubiquitination assays, fractionation, reporter assays

    PMID:28947420 PMID:29891922

    Open questions at the time
    • Determinants selecting K48 versus K63 chain output on different substrates not defined
  13. 2017 High

    Established reciprocal YAP–SKP2 regulation, with YAP transcribing SKP2 under mechanical cues and inducing its Akt/p300-dependent cytosolic acetylation to drive polyploidy and oncogenesis.

    Evidence ChIP, reporter assays, fractionation, genetic epistasis, mouse liver tumor model

    PMID:28486106 PMID:28673931

    Open questions at the time
    • Integration of transcriptional versus post-translational arms in a single tissue not fully dissected
  14. 2018 Medium

    Implicated SKP2-mediated K63 ubiquitination of AKT in PI3K-inhibitor resistance and showed SKP2 acts as an autophagy adaptor degrading IKKβ to suppress NF-κB.

    Evidence AKT ubiquitination assays, kinase-inhibitor and xenograft studies; co-IP and NF-κB reporter assays

    PMID:29474632 PMID:29535262

    Open questions at the time
    • Direct AKT ubiquitination site mapping limited
    • Adaptor versus ligase contributions to IKKβ turnover not separated
  15. 2019 Medium

    Broadened the SKP2 proteolytic substrate set to apoptosis and metabolic regulators (BECN1, PDCD4) and showed K63-AKT ubiquitination promotes mitochondrial glycolysis and chemoresistance.

    Evidence K48/K63 ubiquitination assays, complex characterization, fractionation, xenograft and viral infection models

    PMID:30760284 PMID:31435020 PMID:31852899

    Open questions at the time
    • Composition and regulation of the FKBP51/PHLPP/AKT1/BECN1 heterocomplex incompletely defined
  16. 2019 High

    Demonstrated lineage-specific transcriptional induction of SKP2 (by Notch/pre-TCR) drives p27 degradation in developing thymocytes, and identified ISG15/USP18 as cell-cycle-linked SKP2 stability regulators.

    Evidence Genetic mouse models, T-cell development and ubiquitination assays; co-IP and stability assays

    PMID:30858391 PMID:31451788

    Open questions at the time
    • Redundancy with Fbxl12 in p27 turnover not quantitatively partitioned
  17. 2020 High

    Coupled SKP2 to metabolic oscillation by showing cell-cycle-dependent K48 degradation of IDH1/2, and connected SKP2 to AR stability and ovulation gene regulation via PGK1.

    Evidence Ubiquitination assays, metabolic flux analysis, cell-cycle synchronization, SKP2 knockout; co-IP and GST pulldown

    PMID:32669607 PMID:33096483

    Open questions at the time
    • Whether IDH and AR effects share regulatory inputs not addressed
  18. 2021 High

    Resolved a CKS1-independent route for SKP2 substrate targeting via direct cyclin A engagement and defined deubiquitylase control of SKP2 by USP2 and USP10, including a paradoxical USP2-driven substrate co-stabilization.

    Evidence Complex reconstitution and structural mapping; DUB screen, co-IP, half-life assays, inhibitors, in vivo models

    PMID:33422522 PMID:34425107 PMID:34599966

    Open questions at the time
    • Structural basis for USP2 disrupting SKP2–substrate binding not solved
  19. 2021 Medium

    Identified NUCKS1 as a mitogen- and p53-responsive transcriptional activator of SKP2, and placed SKP2 upstream of β-catenin in hematopoietic stem cell homing.

    Evidence ChIP, reporter and cell-cycle assays, genetic epistasis; microarray and HSC transplantation

    PMID:24561244 PMID:34845229

    Open questions at the time
    • Mechanism by which SKP2 controls β-catenin levels not defined
  20. 2022 Medium

    Showed SKP2 can stabilize substrates by competing with rival E3s (Mcl-1 vs FBW7) and that nuclear FAK/Fzr1 directs SKP2 turnover to regulate vascular proliferation.

    Evidence CRISPR KO, co-IP, ubiquitination assays, xenograft and wire-injury models

    PMID:33839758 PMID:35301297

    Open questions at the time
    • Direct competition versus indirect effects on FBW7 substrate access not fully separated
  21. 2023 Medium

    Extended SKP2 substrate protection and K63-activation paradigms to immunometabolism and ferroptosis, including AhR-driven SKP2 induction promoting Lkb1 K63 ubiquitination and Treg generation, and K48 ubiquitination of SLC3A2 suppressing ferroptosis.

    Evidence Co-IP, K48/K63 ubiquitination assays, FAO and ferroptosis assays, reporter assays, in vivo disease models

    PMID:36694914 PMID:36930164 PMID:37779163 PMID:39079969

    Open questions at the time
    • Some claims rest on single-lab pharmacology with limited direct mechanistic resolution
    • Tissue specificity of opposing K48/K63 outputs unresolved
  22. 2024 Medium

    Defined O-GlcNAcylation as a SKP2-stabilizing modification enhancing SKP1 binding and extended the substrate-protection model to PSPC1 and NLRP3 inflammasome control.

    Evidence Mass spec, Ser34 mutagenesis, ubiquitination assays, co-IP, AAV9 in vivo delivery

    PMID:38360141 PMID:38396292 PMID:38698431

    Open questions at the time
    • Crosstalk between O-GlcNAcylation and acetylation/phosphorylation in setting SKP2 levels not integrated

Open questions

Synthesis pass · forward-looking unresolved questions
  • What molecular features dictate whether SKP2 directs K48-linked degradative versus K63-linked activating ubiquitination on a given substrate, and how the converging post-translational modifications (acetylation, O-GlcNAcylation, phosphorylation) are integrated to set SKP2 localization and activity, remain unresolved.
  • No unified structural model of chain-type selection
  • No quantitative hierarchy among SKP2-stabilizing modifications
  • Substrate competition logic with rival E3s not generalized

Mechanism profile

Synthesis pass · controlled-vocabulary classification · explore literature graph →
Molecular activity
GO:0140096 catalytic activity, acting on a protein 6 GO:0016874 ligase activity 3 GO:0060090 molecular adaptor activity 3 GO:0140110 transcription regulator activity 1
Localization
GO:0005829 cytosol 4 GO:0005634 nucleus 3
Pathway
R-HSA-1640170 Cell Cycle 6 R-HSA-392499 Metabolism of proteins 4 R-HSA-1430728 Metabolism 3 R-HSA-162582 Signal Transduction 3 R-HSA-9612973 Autophagy 3
Partners
AKTCDK2-CYCLIN ACKS1P27KIP1SKP1USP2VHLYAP
Complex memberships
SCF(SKP2) E3 ubiquitin ligase

Evidence

Reading pass · 46 per-paper findings extracted from the source corpus
Year Finding Method Journal Conf PMIDs
2001 Cks1 (CDK subunit 1) is an essential accessory protein required for SCF(Skp2)-mediated ubiquitination of phospho-Thr187-p27; Cks1 binds directly to Skp2 and greatly increases binding of T187-phosphorylated p27 to Skp2, reconstituting ubiquitin ligation of p27 in a fully purified system. Biochemical reconstitution with purified components, in vitro ubiquitination assay, binding assays Nature cell biology High 11231585
2001 Skp2 accumulation depends on both cell adhesion to the ECM and growth factors; ectopic Skp2 in nonadherent G1 cells downregulates p27, drives S-phase entry and cell division, establishing Skp2 as a key mediator of adhesion-dependent cell cycle progression. Ectopic expression, cell cycle analysis, Western blot, loss-of-adhesion assays The Journal of cell biology High 11425869
2003 Skp2 ubiquitylates Myc, regulating its stability and degradation; additionally, Skp2 acts as a transcriptional coactivator for Myc by recognizing an essential element in the Myc activation domain and activating Myc target genes. Ubiquitination assay, transcriptional reporter assays, co-immunoprecipitation Molecular cell Medium 12769843
2003 SKP2 associates with p130 (a retinoblastoma family member) and promotes its polyubiquitylation and proteasomal degradation during the cell cycle, identifying p130 as a substrate of SCF(SKP2). Co-immunoprecipitation, ectopic expression, ubiquitination assay, protein half-life analysis Oncogene Medium 12717421
2003 GA-binding protein (GABP) binds the Skp2 promoter in a cell cycle-dependent manner and is required for cell cycle-dependent transcription of Skp2; overexpression of GABPβ increases Skp2 promoter activity and siRNA knockdown of GABP reduces it. Promoter-reporter assay, EMSA, site-directed mutagenesis, ChIP, siRNA knockdown Cancer research High 12907639
2004 Eight amino acid residues in two discrete regions of Skp2 form the functional binding interface for Cks1; mutation of any of these residues abolishes Cks1 association and negates Skp2-dependent p27 ubiquitination, including residues in the flexible C-terminal tail. Site-directed mutagenesis, binding assays, in vitro ubiquitination assay The Journal of biological chemistry High 15452136
2004 Genetic epistasis in mice shows that loss of p27 (a single Skp2 substrate) rescues the cell size, DNA content, and proliferation defects observed in Skp2 knockout hepatocytes, establishing p27 as the principal downstream effector of SCF(Skp2) for cell cycle control. Genetic epistasis: Skp2 knockout vs. skp2-KO/p27T187A knock-in double mutant mice, histological and cell cycle analysis Genes & development High 15520280
2006 The Skp2 gene contains a functional E2F response element; E2F1 directly induces endogenous Skp2 expression, and antisense-mediated E2F1 knockdown reduces Skp2 in tumor cell lines, establishing Skp2 as a transcriptional target of E2F. Promoter-reporter assay, ectopic E2F1 expression, antisense knockdown, chromatin analysis Oncogene Medium 16331253
2008 Androgen receptor (AR) stabilizes Skp2 by blocking D-box-dependent degradation of Skp2; Skp2 is an essential downstream effector of AR-driven proliferation in androgen-dependent prostate cancer cells, independently of AR's differentiation-promoting functions. Co-immunoprecipitation, ectopic expression, loss-of-function (siRNA/dominant-negative), cell proliferation assays Journal of cell science Medium 18628304
2011 pVHL (von Hippel-Lindau protein) destabilizes Skp2 through its β-domain interaction with Skp2, promoting proteasome-dependent Skp2 degradation independently of pVHL's E3 ligase activity; pVHL antagonizes Akt-mediated phosphorylation that stabilizes Skp2, and DNA damage induces pVHL-dependent Skp2 degradation. Co-immunoprecipitation, ectopic expression, protein half-life assay, mutagenesis, VHL-null renal cell carcinoma reconstitution Oncogene Medium 21358672
2012 Skp2 is acetylated by p300 at K68 and K71; this acetylation is reversed by SIRT3 deacetylase, impairs Cdh1-mediated proteolysis, increases Skp2 stability, and promotes cytoplasmic retention of Skp2 via its nuclear localization signal. Cytoplasmic Skp2 ubiquitinates and destroys E-cadherin, promoting cell migration. Mass spectrometry, acetylation-mimetic and acetylation-dead mutagenesis, co-immunoprecipitation, ubiquitination assay, cell fractionation, migration assay, in vivo tumorigenesis Cell High 22770219
2015 Skp2 SCF complex ubiquitinates and degrades macroH2A1 (mH2A1); loss of mH2A1 promotes CDK8 gene expression, and CDK8 in turn facilitates Skp2-mediated p27 ubiquitination and degradation, establishing a Skp2-mH2A1-CDK8 axis regulating G2/M transition. Co-immunoprecipitation, ubiquitination assay, western blot, mouse tumor models with genetic rescue Nature communications High 25818643
2016 SKP2 ubiquitinates CARM1 (via K48-linked chains) in the nucleus under nutrient-rich conditions, promoting its proteasomal degradation; nutrient starvation activates AMPK, which phosphorylates FOXO3a to transcriptionally repress SKP2, thereby stabilizing CARM1 to drive autophagy-gene transcription through TFEB. Co-immunoprecipitation, ubiquitination assay, genetic knockdown/knockout, AMPK inhibitor/activator treatment, ChIP, genome-wide analysis Nature High 27309807
2016 Skp2 inactivation decreases JARID1B K63-linked ubiquitination (mediated by TRAF6) — meaning Skp2 protects JARID1B from TRAF6-dependent ubiquitination — thereby reducing JARID1B demethylase activity and increasing H3K4me3, linked to prostate cancer suppression and senescence induction. Co-immunoprecipitation, ubiquitination assay (K63-linked), mouse tumor models (Pten/Trp53 knockout), Skp2 knockdown Oncotarget Medium 25596733
2016 SKP2 loss destabilizes EZH2 by allowing TRAF6-mediated K63-linked ubiquitination of EZH2, promoting its degradation; Skp2 protects EZH2 from TRAF6-dependent ubiquitination in prostate cancer cells and in vivo mouse prostate tumor models. Co-immunoprecipitation, K63-ubiquitination assay, in vitro ubiquitination with catalytic dead TRAF6 mutant, mouse models Oncogene Medium 27869166
2017 YAP (Hippo pathway effector) induces p300-mediated acetylation of Skp2 via Akt signaling; acetylated Skp2 is exclusively cytosolic, causing p27 accumulation (mitotic arrest, polyploidy) while also degrading FoxO1/3 pro-apoptotic factors, leading to polyploid cell division and oncogenesis. Co-immunoprecipitation, acetylation assay, cell fractionation, genetic epistasis (Akt/Skp2 depletion), mouse liver tumorigenesis model Cancer cell High 28486106
2017 YAP directly promotes Skp2 transcription in response to mechanical cues (matrix stiffness); YAP inactivation downregulates Skp2, causing p21/p27 accumulation and cell cycle exit (G0), whereas Skp2 reconstitution rescues proliferation. ChIP, luciferase reporter, siRNA knockdown, Skp2 reconstitution, 3D culture system The EMBO journal Medium 28673931
2017 Skp2 promotes K63-linked polyubiquitination of MTH1 (stabilization, not degradation) via the SCF complex; this increases MTH1 protein levels in melanoma cells and protects them from oxidative stress-induced DNA damage and apoptosis. Co-immunoprecipitation, ubiquitination assay (K63-linked), Skp2 overexpression/knockdown, SCF inhibition Cancer research Medium 28947420
2018 SCFSKP2 catalyzes K63-linked (non-proteolytic) polyubiquitination of YAP at K321 and K497, which enhances YAP interaction with TEAD and promotes YAP nuclear localization and transcriptional activity independently of Hippo signaling; the deubiquitinase OTUD1 reverses this modification. Co-immunoprecipitation, K63-ubiquitination assay, mutagenesis of ubiquitination sites, nuclear/cytoplasmic fractionation, transcriptional reporter assays Nature communications High 29891922
2018 Skp2-dependent reactivation of AKT drives resistance to PI3K inhibitors in triple-negative breast cancer; Skp2 ubiquitylates AKT (K63-linked) to reactivate it via IGF-1R/PDK-1/mTORC2 signaling, independently of PI3K activity or PIP3. AKT ubiquitination assay, genetic knockdown, kinase inhibitor treatment, xenograft tumor growth assay Science signaling Medium 29535262
2018 SKP2 functions as an adaptor to promote interaction between active IKKβ and the autophagic cargo receptor p62, mediating IKKβ degradation via selective autophagy and thereby suppressing NF-κB activation. Co-immunoprecipitation, genetic knockdown (siRNA/KO), Western blot, NF-κB reporter assay Journal of molecular cell biology Medium 29474632
2019 SKP2 executes K48-linked polyubiquitination of BECN1 (Beclin1), promoting its proteasomal degradation; SKP2 activity is regulated by phosphorylation within a heterocomplex involving FKBP51, PHLPP, AKT1, and BECN1. SKP2 inhibition enhances autophagic flux and reduces MERS-CoV replication. Co-immunoprecipitation, ubiquitination assay (K48-linked), genetic/pharmacological SKP2 inhibition, autophagic flux assay, viral infection assay Nature communications High 31852899
2019 SKP2 promotes PDCD4 phosphorylation, ubiquitination, and proteasomal degradation; this suppresses apoptosis and enhances DNA-damage response in breast cancer cells, establishing PDCD4 as a ubiquitination substrate of SKP2. Mass spectrometry, reciprocal co-immunoprecipitation, ubiquitination assay, SKP2 overexpression/knockdown, in vivo xenograft Journal of experimental & clinical cancer research Medium 30760284
2019 Skp2 promotes K63-linked ubiquitination of Akt, enhancing Akt activation, mitochondrial localization, HK2 phosphorylation (Thr473), and HK2 mitochondrial localization, thereby promoting glycolysis and cisplatin resistance. Co-immunoprecipitation, K63-ubiquitination assay, ectopic expression/knockdown, mitochondrial fractionation, xenograft model Oncogene Medium 31435020
2019 Notch and pre-TCR signaling cooperatively induce expression of the F-box protein Fbxl1 (SKP2/FBXL1) and Fbxl12; both SCF complexes target Cdkn1b (p27) for polyubiquitination and proteasomal degradation to drive proliferation of β-selected thymocytes, with Notch specifically inducing Fbxl1 transcription. Genetic mouse models, T-cell development assays, ubiquitination assay, transcriptional analysis Nature immunology High 31451788
2019 USP18 (a Skp2 substrate) stabilizes SKP2 protein; free ISG15 disrupts the USP18-SKP2 complex, driving SKP2 to degradation and/or ISGylation. USP18 silencing slows S-phase entry, showing USP18 and ISG15 as SKP2 regulators impacting cell cycle progression. Co-immunoprecipitation, siRNA knockdown, protein stability assay, cell cycle analysis Scientific reports Medium 30858391
2020 Skp2 promotes K48-linked ubiquitination and proteasomal degradation of IDH1 and IDH2 (key TCA cycle enzymes) in a cell cycle-dependent manner, coupling cell cycle phase to metabolic oscillation between glycolysis (S phase, high Skp2) and TCA cycle (G1 phase, low Skp2). Co-immunoprecipitation, ubiquitination assay, metabolic flux analysis, cell cycle synchronization, SKP2 knockout Cell research High 32669607
2020 PGK1 interacts with AR and inhibits AR ubiquitination levels in an E3 ligase SKP2-dependent manner, thereby increasing AR protein stability in granulosa cells; this promotes AR nuclear translocation and regulates ovulation-related gene expression. Co-immunoprecipitation, GST pulldown, ubiquitination assay, siRNA knockdown, Western blot EBioMedicine Medium 33096483
2021 NUCKS1 transcription factor is recruited to chromatin upon mitogenic stimulation to activate SKP2 expression, leading to p21/p27 degradation and S-phase entry; DNA damage induces p53-dependent NUCKS1 repression, reducing SKP2 and causing cell cycle arrest. ChIP, siRNA knockdown, reporter assay, cell cycle analysis, genetic epistasis Nature communications High 34845229
2021 USP2 is a deubiquitylase that binds SKP2 via the leucine-rich repeat substrate-binding domain, deubiquitylates and stabilizes SKP2 protein; unexpectedly, USP2-stabilized SKP2 disrupts SKP2-substrate binding, leading to co-stabilization of p21 and p27. DUB screen, co-immunoprecipitation, ubiquitination assay, protein half-life assay (cycloheximide chase), siRNA knockdown, small-molecule inhibitor The Journal of biological chemistry Medium 34425107
2021 Reconstitution of stable complexes shows SKP1-SKP2 interacts with CDK2-cyclin A via a direct SKP2 N-terminal motif that engages a site on cyclin A not present in cyclin B or E, providing a CKS1-independent mechanism to stabilize the complex and fine-tune p27KIP1 degradation by cyclin A specifically. Protein complex reconstitution, structural mapping, mutagenesis, biochemical binding assays Journal of molecular biology High 33422522
2021 SKP2 deficiency reduces β-catenin expression and its target genes; knockdown of β-catenin mimics the defect in hematopoietic stem cell (HSC) homing seen in Skp2-deficient mice, placing Skp2 upstream of β-catenin in HSC homing. Microarray, co-immunoprecipitation/Western blot, HSC transplantation assay, β-catenin knockdown epistasis Biochemical and biophysical research communications Medium 24561244
2022 Skp2 stabilizes Mcl-1 by competing with FBW7-mediated ubiquitination of Mcl-1; Skp2 deficiency facilitates FBW7-mediated Mcl-1 ubiquitination and degradation, enhancing radiation-induced apoptosis in colorectal cancer cells. CRISPR-Cas9 knockout, co-immunoprecipitation, ubiquitination assay, xenograft model, apoptosis assay Cell death & disease Medium 35301297
2022 Nuclear FAK N-terminal domain interacts with Skp2 and the APC/C activator Fzr1 (Cdh1) to promote ubiquitination and degradation of both Skp2 and Fzr1, thereby controlling p27 and p21 levels in vascular smooth muscle cells and restraining neointima formation. Co-immunoprecipitation, genetic FAK inhibition/FAK kinase-dead knock-in, cell fractionation, wire injury mouse model Cardiovascular research Medium 33839758
2022 TRIM33 protects AR from Skp2-mediated ubiquitination and proteasomal degradation in prostate cancer cells, stabilizing AR protein; identified by proteomics and confirmed by ubiquitination assay. Proteomics (mass spectrometry), co-immunoprecipitation, ubiquitination assay, knockdown, cell cycle/apoptosis assay EMBO reports Medium 35785414
2023 SKP2 depletion reduces K48-linked ubiquitination of SLC3A2, impairing its membrane localization and cystine/glutamate exchange function, thereby triggering ferroptosis in pulmonary epithelial cells; sepsis activates MEK/ERK to suppress Skp2, driving this pathway. Co-immunoprecipitation, ubiquitination assay (K48-linked), membrane fractionation, ferroptosis assay, lipid nanoparticle mRNA delivery in mouse model Cellular and molecular life sciences Medium 39079969
2024 SKP2 is O-GlcNAcylated at Ser34 by OGT; this modification stabilizes SKP2 by reducing APC-CDH1-mediated ubiquitination and degradation, and also enhances SKP2 binding to SKP1, increasing the ubiquitin ligase function and promoting p27/p21 degradation and G1-S transition in hepatocellular carcinoma. Mass spectrometry, co-immunoprecipitation, mutagenesis (Ser34 site), ubiquitination assay, cell cycle analysis Oncogene Medium 38396292
2024 SKP2 depletion in pancreatic ductal adenocarcinoma (PDAC) results in polyubiquitination of PSPC1 by TRIM21, promoting its degradation; SKP2 normally protects PSPC1 from TRIM21-mediated ubiquitination, thereby promoting PDAC metastasis. Co-immunoprecipitation, ubiquitination assay, SMIP004 inhibitor treatment, migration assay Cancer letters Medium 38360141
2021 USP10 binds Skp2 in the cytoplasm and removes polyubiquitin from Skp2, stabilizing Skp2 protein; USP10 deficiency reduces Skp2 levels, causing cell cycle arrest in vascular smooth muscle cells and reducing neointima formation. Co-immunoprecipitation, protein half-life assay (cycloheximide chase), siRNA knockdown, cell cycle analysis, mouse carotid ligation model The Journal of biological chemistry Medium 34599966
2023 SKP2 promotes K63-linked ubiquitination of Lkb1, facilitating formation of the Strad-Mo25-Lkb1 complex and enhancing Lkb1-mediated fatty acid oxidation (FAO), which drives Treg cell generation; this pathway is transcriptionally induced by AhR binding to the Skp2 promoter. Co-immunoprecipitation, K63-ubiquitination assay, luciferase reporter (AhR binding to Skp2 promoter), FAO metabolic assay, flow cytometry (Treg induction), in vivo colitis/arthritis models Immunology Medium 36930164
2009 Skp2 binds to TIS21/BTG2 via its leucine-rich repeat (LRR) domain and promotes TIS21 polyubiquitination and proteasomal degradation; LRR-deleted Skp2 or C-terminus-deleted TIS21 fail to interact, prolonging TIS21 half-life. FoxM1 transcriptionally regulates Skp2 expression upstream of this pathway. Co-immunoprecipitation, ubiquitination assay, mutagenesis (LRR-deleted Skp2 and TIS21ΔC), protein half-life assay, reporter assay Experimental cell research Medium 19615363
2016 Skp2 promotes ubiquitin-proteasome-mediated degradation of the osteogenic transcription factor Runx2; Skp2 physically interacts with Runx2 (co-IP in heterologous and physiological systems) and Skp2-mediated Runx2 downregulation reduces osteoblast differentiation. Co-immunoprecipitation, ubiquitination assay, promoter-reporter assay, osteoblast differentiation assay Biochimica et biophysica acta Medium 26778333
2023 SKP2 mediates K63-linked ubiquitination of Akt to promote Akt activity; this is inhibited by gastrodin-mediated Akt suppression, and SKP2 depletion reduces K63-Akt ubiquitination and glycolysis in cisplatin-resistant oral squamous cell carcinoma. Co-immunoprecipitation, K63-ubiquitination assay, siRNA knockdown, xenograft model Cell death discovery Low 37779163
2024 SKP2 interacts with NLRP3 and mediates its K48-linked ubiquitination, promoting NLRP3 proteasomal degradation; HSPA8 suppression reduces SKP2, attenuating NLRP3 ubiquitination and thereby activating NLRP3 inflammasome-mediated pyroptosis in alveolar epithelial cells. Co-immunoprecipitation, ubiquitination assay, AAV9-SKP2 in vivo delivery, genetic knockdown Cell & bioscience Medium 38698431
2023 In FN-RMS, MYOD binds an intronic enhancer of SKP2 to transcriptionally upregulate it; SKP2 in turn directly targets both p27Kip1 and p57Kip2 for ubiquitination and degradation, promoting cell cycle progression and preventing myogenic differentiation. ChIP, luciferase reporter, co-immunoprecipitation, ubiquitination assay, genetic knockdown, in vivo tumor model Nature communications Medium 38102140
2023 SKP2 interacts with PHLPP1 and promotes its ubiquitination and degradation, activating AKT-related pathways; cytoplasmic translocation of SKP2 is regulated reciprocally by AKT activity, establishing a feedback loop between SKP2 and AKT via PHLPP1. Co-immunoprecipitation, ubiquitination assay, cell fractionation, genetic knockdown, xenograft model Molecules and cells Medium 36694914

Source papers

Stage 0 corpus · 100 papers · ranked by NIH iCite citations
Year Title Journal Citations PMID
2008 Deregulated proteolysis by the F-box proteins SKP2 and beta-TrCP: tipping the scales of cancer. Nature reviews. Cancer 816 18500245
2003 Skp2 regulates Myc protein stability and activity. Molecular cell 442 12769843
2001 The cell-cycle regulatory protein Cks1 is required for SCF(Skp2)-mediated ubiquitinylation of p27. Nature cell biology 430 11231585
2016 AMPK-SKP2-CARM1 signalling cascade in transcriptional regulation of autophagy. Nature 383 27309807
2019 SKP2 attenuates autophagy through Beclin1-ubiquitination and its inhibition reduces MERS-Coronavirus infection. Nature communications 293 31852899
2012 Acetylation-dependent regulation of Skp2 function. Cell 191 22770219
2004 Skp2-dependent degradation of p27kip1 is essential for cell cycle progression. Genes & development 170 15520280
2018 SKP2- and OTUD1-regulated non-proteolytic ubiquitination of YAP promotes YAP nuclear localization and activity. Nature communications 147 29891922
2017 Hippo Signaling Suppresses Cell Ploidy and Tumorigenesis through Skp2. Cancer cell 140 28486106
2020 The Skp2 Pathway: A Critical Target for Cancer Therapy. Seminars in cancer biology 138 32014608
2020 Skp2 in the ubiquitin-proteasome system: A comprehensive review. Medicinal research reviews 119 32391596
2001 Role of the F-box protein Skp2 in adhesion-dependent cell cycle progression. The Journal of cell biology 118 11425869
2006 F-box protein Skp2: a novel transcriptional target of E2F. Oncogene 117 16331253
2013 STAT3 interacts with Skp2/p27/p21 pathway to regulate the motility and invasion of gastric cancer cells. Cellular signalling 108 23333463
2011 Skp2: a novel potential therapeutic target for prostate cancer. Biochimica et biophysica acta 107 21963805
2010 Regulation of Skp2 expression and activity and its role in cancer progression. TheScientificWorldJournal 99 20526532
2003 SKP2 associates with p130 and accelerates p130 ubiquitylation and degradation in human cells. Oncogene 96 12717421
2019 SKP2 promotes breast cancer tumorigenesis and radiation tolerance through PDCD4 ubiquitination. Journal of experimental & clinical cancer research : CR 93 30760284
2015 Skp2-macroH2A1-CDK8 axis orchestrates G2/M transition and tumorigenesis. Nature communications 93 25818643
2021 The Hippo Pathway Effector YAP Promotes Ferroptosis via the E3 Ligase SKP2. Molecular cancer research : MCR 90 33707306
2020 Skp2 dictates cell cycle-dependent metabolic oscillation between glycolysis and TCA cycle. Cell research 87 32669607
2004 Control of DNA synthesis and mitosis by the Skp2-p27-Cdk1/2 axis. Molecular cell 85 15149588
2003 Cell cycle-dependent regulation of the Skp2 promoter by GA-binding protein. Cancer research 77 12907639
2019 Skp2-mediated ubiquitination and mitochondrial localization of Akt drive tumor growth and chemoresistance to cisplatin. Oncogene 76 31435020
2019 RNA-binding protein NONO promotes breast cancer proliferation by post-transcriptional regulation of SKP2 and E2F8. Cancer science 75 31733123
2017 MYC Modulation around the CDK2/p27/SKP2 Axis. Genes 73 28665315
2017 Mechanical cue-induced YAP instructs Skp2-dependent cell cycle exit and oncogenic signaling. The EMBO journal 70 28673931
2004 Skp2 and p27kip1 expression in melanocytic nevi and melanoma: an inverse relationship. Journal of cutaneous pathology 68 15491322
2013 Salinomycin induces cell death via inactivation of Stat3 and downregulation of Skp2. Cell death & disease 67 23807222
2015 The role of Skp2 and its substrate CDKN1B (p27) in colorectal cancer. Journal of gastrointestinal and liver diseases : JGLD 66 26114183
2021 The NUCKS1-SKP2-p21/p27 axis controls S phase entry. Nature communications 63 34845229
2006 Significance of skp2 expression in primary breast cancer. Clinical cancer research : an official journal of the American Association for Cancer Research 63 16489076
2011 Novel roles of Skp2 E3 ligase in cellular senescence, cancer progression, and metastasis. Chinese journal of cancer 61 22200179
2015 E3 ubiquitin ligase Skp2 as an attractive target in cancer therapy. Frontiers in bioscience (Landmark edition) 55 25553462
2008 Absence of SKP2 expression attenuates BCR-ABL-induced myeloproliferative disease. Blood 55 18559973
2018 Skp2-dependent reactivation of AKT drives resistance to PI3K inhibitors. Science signaling 54 29535262
2016 SKP2 loss destabilizes EZH2 by promoting TRAF6-mediated ubiquitination to suppress prostate cancer. Oncogene 54 27869166
2018 Down-regulation of Skp2 expression inhibits invasion and lung metastasis in osteosarcoma. Scientific reports 51 30250282
2020 Novel PGK1 determines SKP2-dependent AR stability and reprograms granular cell glucose metabolism facilitating ovulation dysfunction. EBioMedicine 49 33096483
2015 SKP2 inactivation suppresses prostate tumorigenesis by mediating JARID1B ubiquitination. Oncotarget 48 25596733
2017 Skp2-Mediated Stabilization of MTH1 Promotes Survival of Melanoma Cells upon Oxidative Stress. Cancer research 47 28947420
2004 Downregulation of Skp2 and p27/Kip1 synergistically induces apoptosis in T98G glioblastoma cells. Journal of molecular medicine (Berlin, Germany) 47 15605273
2016 Skp2 Inhibitors: Novel Anticancer Strategies. Current medicinal chemistry 43 27160538
2022 Skp2 stabilizes Mcl-1 and confers radioresistance in colorectal cancer. Cell death & disease 42 35301297
2016 Skp2 is over-expressed in breast cancer and promotes breast cancer cell proliferation. Cell cycle (Georgetown, Tex.) 42 27111245
2016 Skp2 inhibits osteogenesis by promoting ubiquitin-proteasome degradation of Runx2. Biochimica et biophysica acta 41 26778333
2020 Skp2 modulates proliferation, senescence and tumorigenesis of glioma. Cancer cell international 40 32165861
2007 High Skp2 expression characterizes high-risk neuroblastomas independent of MYCN status. Clinical cancer research : an official journal of the American Association for Cancer Research 39 17652624
2021 Emerging Roles of SKP2 in Cancer Drug Resistance. Cells 38 34068643
2020 Rb and p53-Deficient Myxofibrosarcoma and Undifferentiated Pleomorphic Sarcoma Require Skp2 for Survival. Cancer research 37 32161142
2019 Therapeutic targeting of the E3 ubiquitin ligase SKP2 in T-ALL. Leukemia 36 31772299
2019 USP18 and ISG15 coordinately impact on SKP2 and cell cycle progression. Scientific reports 35 30858391
2016 Skp2 is associated with paclitaxel resistance in prostate cancer cells. Oncology reports 34 27175797
2005 Skp2, the FoxO1 hunter. Cancer cell 32 15766658
2018 SKP2 attenuates NF-κB signaling by mediating IKKβ degradation through autophagy. Journal of molecular cell biology 31 29474632
2011 Involvement of the SKP2-p27(KIP1) pathway in suppression of cancer cell proliferation by RECK. Oncogene 31 22158033
2024 Ginkgo biloba extract alleviates deltamethrin-induced testicular injury by upregulating SKP2 and inhibiting Beclin1-independent autophagy. Phytomedicine : international journal of phytotherapy and phytopharmacology 30 39550920
2019 Notch and the pre-TCR coordinate thymocyte proliferation by induction of the SCF subunits Fbxl1 and Fbxl12. Nature immunology 30 31451788
2012 Stat3 induces oncogenic Skp2 expression in human cervical carcinoma cells. Biochemical and biophysical research communications 29 22252296
2011 Skp2 is required for incretin hormone-mediated β-cell proliferation. Molecular endocrinology (Baltimore, Md.) 29 21980072
2012 Skp2 expression unfavorably impacts survival in resectable esophageal squamous cell carcinoma. Journal of translational medicine 28 22533738
2021 USP2 is an SKP2 deubiquitylase that stabilizes both SKP2 and its substrates. The Journal of biological chemistry 27 34425107
2022 SKP2 drives the sensitivity to neddylation inhibitors and cisplatin in malignant pleural mesothelioma. Journal of experimental & clinical cancer research : CR 26 35197103
2019 Gartanin is a novel NEDDylation inhibitor for induction of Skp2 degradation, FBXW2 expression, and autophagy. Molecular carcinogenesis 26 31782573
2008 An AR-Skp2 pathway for proliferation of androgen-dependent prostate-cancer cells. Journal of cell science 26 18628304
2022 FAK in the nucleus prevents VSMC proliferation by promoting p27 and p21 expression via Skp2 degradation. Cardiovascular research 25 33839758
2022 TRIM33 drives prostate tumor growth by stabilizing androgen receptor from Skp2-mediated degradation. EMBO reports 25 35785414
2021 CircCRIM1 Promotes Hepatocellular Carcinoma Proliferation and Angiogenesis by Sponging miR-378a-3p and Regulating SKP2 Expression. Frontiers in cell and developmental biology 25 34869393
2023 Gastrodin overcomes chemoresistance via inhibiting Skp2-mediated glycolysis. Cell death discovery 24 37779163
2024 Skp2: A critical molecule for ubiquitination and its role in cancer. Life sciences 23 38184273
2023 AhR activation promotes Treg cell generation by enhancing Lkb1-mediated fatty acid oxidation via the Skp2/K63-ubiquitination pathway. Immunology 23 36930164
2011 von Hippel-Lindau protein promotes Skp2 destabilization on DNA damage. Oncogene 23 21358672
2024 Suppression of Skp2 contributes to sepsis-induced acute lung injury by enhancing ferroptosis through the ubiquitination of SLC3A2. Cellular and molecular life sciences : CMLS 22 39079969
2021 The interaction of SKP2 with p27 enhances the progression and stemness of osteosarcoma. Annals of the New York Academy of Sciences 22 33594717
2020 Skp2 depletion reduces tumor-initiating properties and promotes apoptosis in synovial sarcoma. Translational oncology 21 32623326
2024 SKP2 promotes the metastasis of pancreatic ductal adenocarcinoma by suppressing TRIM21-mediated PSPC1 degradation. Cancer letters 20 38360141
2024 O-GlcNAcylation of E3 ubiquitin ligase SKP2 promotes hepatocellular carcinoma proliferation. Oncogene 20 38396292
2023 MYOD-SKP2 axis boosts tumorigenesis in fusion negative rhabdomyosarcoma by preventing differentiation through p57Kip2 targeting. Nature communications 20 38102140
2021 Discriminative SKP2 Interactions with CDK-Cyclin Complexes Support a Cyclin A-Specific Role in p27KIP1 Degradation. Journal of molecular biology 19 33422522
2021 DNAJC5 promotes hepatocellular carcinoma cells proliferation though regulating SKP2 mediated p27 degradation. Biochimica et biophysica acta. Molecular cell research 19 33662413
2021 Skp2 and Slug Are Coexpressed in Aggressive Prostate Cancer and Inhibited by Neddylation Blockade. International journal of molecular sciences 19 33799604
2019 SKP2, positively regulated by circ_ODC1/miR-422a axis, promotes the proliferation of retinoblastoma. Journal of cellular biochemistry 19 31297892
2017 Inhibition of Skp2 suppresses the proliferation and invasion of osteosarcoma cells. Oncology reports 19 28627672
2021 USP10 exacerbates neointima formation by stabilizing Skp2 protein in vascular smooth muscle cells. The Journal of biological chemistry 18 34599966
2009 Skp2 enhances polyubiquitination and degradation of TIS21/BTG2/PC3, tumor suppressor protein, at the downstream of FoxM1. Experimental cell research 18 19615363
2022 Aurora-A/FOXO3A/SKP2 axis promotes tumor progression in clear cell renal cell carcinoma and dual-targeting Aurora-A/SKP2 shows synthetic lethality. Cell death & disease 17 35831273
2020 Paeoniflorin inhibits cell viability and invasion of liver cancer cells via inhibition of Skp2. Oncology letters 17 32256812
2019 Skp2 inhibitor SKPin C1 decreased viability and proliferation of multiple myeloma cells and induced apoptosis. Brazilian journal of medical and biological research = Revista brasileira de pesquisas medicas e biologicas 17 31038581
2004 Crashing waves of destruction: the cell cycle and APC(Cdh1) regulation of SCF(Skp2). Cancer cell 17 15093536
2024 SKping cell cycle regulation: role of ubiquitin ligase SKP2 in hematological malignancies. Frontiers in oncology 16 38559562
2014 E3-ligase Skp2 regulates β-catenin expression and maintains hematopoietic stem cell homing. Biochemical and biophysical research communications 16 24561244
2004 Molecular and biochemical characterization of the Skp2-Cks1 binding interface. The Journal of biological chemistry 16 15452136
2023 SKP2 Contributes to AKT Activation by Ubiquitination Degradation of PHLPP1, Impedes Autophagy, and Facilitates the Survival of Thyroid Carcinoma. Molecules and cells 15 36694914
2022 Inhibition of USP14 enhances anti-tumor effect in vemurafenib-resistant melanoma by regulation of Skp2. Cell biology and toxicology 15 35648318
2020 Targeting SKP2/Bcr-Abl pathway with Diosmetin suppresses chronic myeloid leukemia proliferation. European journal of pharmacology 15 32679184
2017 SKP2 Activation by Thyroid Hormone Receptor β2 Bypasses Rb-Dependent Proliferation in Rb-Deficient Cells. Cancer research 15 28972075
2024 The suppression of HSPA8 attenuates NLRP3 ubiquitination through SKP2 to promote pyroptosis in sepsis-induced lung injury. Cell & bioscience 14 38698431
2019 Fbxw7 and Skp2 Regulate Stem Cell Switch between Quiescence and Mitotic Division in Lung Adenocarcinoma. BioMed research international 14 31534970
2017 Dysregulated expression of SKP2 and its role in hematological malignancies. Leukemia & lymphoma 14 28797197
2016 Definition of a Skp2-c-Myc Pathway to Expand Human Beta-cells. Scientific reports 14 27380896

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